The present invention relates to 4-alkyl-/4-alkenyl-/4-alkynylmethyl/-1-aryl-cyclohexylamine compounds, to processes for their preparation, to pharmaceutical compositions containing these compounds and to the use of 4-alkyl-/4-alkenyl-/4-alkynylmethyl/-1-aryl-cyclohexylamine compounds for producing pharmaceutical compositions and for treating or inhibiting pain and other specified conditions involving the ORL1 receptor.
The heptadecapeptide nociceptin is an endogenous ligand of the ORL1 (opioid receptor-like) receptor (Meunier et al, Nature 377, 1995, pp. 532 to 535), which belongs to the opioid receptor family and can be found in many regions of the brain and spinal chord and has a high affinity for the ORL1 receptor. The ORL1 receptor is homologous to the ∥, κ and δ opioid receptors, and the amino acid sequence of the nociceptin peptide has a strong similarity to those of the known opioid peptides. The nociceptin induced activation of the receptor leads, via the coupling with Gi/o proteins, to inhibition of adenylate cyclase (Meunier et al, Nature 377, 1995, pp. 532 to 535).
After intracerebroventricular administration, the nociceptin peptide exhibits pronociceptive and hyperalgesic activity in various animal models (Reinscheid et al, Science 270, 1995, pp. 792 to 794). These findings can be described as inhibition of stress-induced analgesia (Mogil et al, Neuroscience 75, 1996, pp. 333 to 337). In this connection, anxiolytic activity of the nociceptin could also be demonstrated (Jenck et al, Proc. Natl. Acad. Sci. USA 94, 1997, 14854 to 14858).
On the other hand, an anti-nociceptive effect of nociceptin could also be demonstrated in various animal models, in particular after intrathecal administration. Nociceptin has an anti-nociceptive effect in various pain models, for example in the tail flick test in mice (King et al, Neurosci. Lett., 223, 1997, 113 to 116). An anti-nociceptive effect of nociceptin, which is of particular interest in that the efficacy of nociceptin increases after axotomy of spinal nerves, could also be demonstrated in models of neuropathic pain. This is in contrast to conventional opioids, of which the efficacy decreases under these conditions (Abdulla and Smith, J. Neurosci., 18, 1998, pp. 9685 to 9684).
The ORL1 receptor is also involved in the regulation of further physiological and pathophysiological processes. These include inter alia learning and memory formation (Manabe et al, Nature, 394, 1997, pp. 577 to 581), Hörvermögen [Hearing capacity] (Nishi et al, EMBO J., 16, 1997, pp. 1858 to 1864) and numerous further processes. In a synopsis by Calo et al (Br. J. Pharmacol., 129, 2000, 1261 to 1283) there is an overview of the indications or biological procedures, in which the ORL1 receptor plays a part or could highly probably play a part. Mentioned inter alia are: analgesia, stimulation and regulation of nutrient absorption, effect on μ-agonists such as morphine, treatment of withdrawal symptoms, reduction of the addiction potential of opioids, anxiolysis, modulation of motor activity, memory disorders, epilepsy; modulation of neurotransmitter release, in particular of glutamate, serotonin and dopamine, and therefore neurodegenerative diseases; influencing the cardiovascular system, triggering an erection, diuresis, anti-natriuresis, electrolyte balance, arterial blood pressure, water-retention disorders, intestinal motility (diarrhoea), relaxation of the respiratory tract, micturation reflex (urinary incontinence). The use of agonists and antagonists such as anoretics, analgesics (also when administered with opioids) or nootropics will also be discussed.
The possibilities for administration of compounds which bind to the ORL1 receptor and activate or inhibit it are correspondingly diverse. In addition thereto, opioid receptors, such as the μ receptor and other sub-types, play an important role in the field of pain therapy but also in the other indications mentioned. It is accordingly advantageous if the compound is also effective with respect to these opioid receptors.